Synthesis and reactions of derivatives of 5-alkyl- and 5-halo-pyrimidines (original) (raw)
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Synthesis and biological activity of 5-fluoro-4'-thiouridine and some related nucleosides
Journal of Medicinal Chemistry, 1975
The synthesis of a series of 4'-thio-5-halogenopyrimidine nucleosides, including the S-flUOrO, chloro, bromo and iodo derivatives, has been carried out by condensation of the 2,4-bis-0-trimethylsilyl derivatives of the corresponding pyrimidine bases with the protected 4-thio-D-ribofuranosyl chloride. Among these, the CY and / 3 anomers of 4'-thio-5-fluorouridine inhibited the growth of leukemia L1210 cells at concentrations of 4 X and 2 X M , respectively, and that of S. faecium at 4 X lom9 and 6 X 10-lo M, respectively. These compounds retained marked activity against strains of S. faecium resistant to M 5-fluorouracil or 5-fluorouridine. As determined in S. faecium cultures, 4'thio-5-fluorouridine decreased the total protein content of the cells more markedly than it did their RNA or DNA content. X-Ray crystallography showed that substitution of sulfur for the oxygen in the carbohydrate ring markedly changes the conformation of that moiety. Because of the pronounced biological activity of 5-fluorinated pyrimidines,' and the fact that the 4'-thio derivatives of various purine nucleoside analogs have been shown to retain their growth inhibitory activity against cells resistant to the corresponding ribofuranosyl analog^,^^^ the synthesis of some 4'-thio-5-halogenopyrimidine nucleosides was undertaken. These compounds were tested for the in vitro growth inhibitory activity which they exert in some tumor and bacterial cell systems. The chemical synthesis of the compounds and the results of their biological evaluation are reported in this paper. A preliminary account of these data has been given.4 Recently,l we reported that 2,9-dimethyl-6,7-benzomorphan (16), not obtainable in the usual way2 from 3-methylpyridine. could be synthesized in 12 steps from phenylace-tonitrile, only the fl isomer being formed. By some modifications of this sequence we have now prepared the 2'-hydroxy relative 18. Described below are the synthesis of 18 and the analgetic and other pharmacologic properties of 16 and 18 and two analogs, 15 and 17.
Synthesis of 6′‐Methyl‐2′‐ O ,4′‐ C ‐methylene‐ α ‐L‐ ribofuranosyl‐pyrimidine Nucleosides
ChemistrySelect, 2019
Herein, we report the efficient synthesis of (6'R)-and (6'S)-6'methyl-2'-O,4'-C-methylene-α-L-ribofuranosyl-thymine, and (6'R)-and (6'S)-6'-methyl-2'-O,4'-C-methylene-α-L-ribofuranosyluracil starting from diacetone glucofuranose in overall yields of 6.3, 4.7, 5.4 and 4.0%, respectively. The key step in the synthesis of stereochemically defined 6'-Me-bicyclic-nucleosides is the nucleophilic addition of methyl group at methylene carbon of 4-C-CH 2 OH moiety of the 4-C-tert-butyldiphenylsilyloxymethylated sugar precursor. Thus, the methyl group was added on the aldehyde obtained from Dess-Martin periodinane oxidation of the precursor alcohol employing AlMe 3 in hexane. Both (6'R)and (6'S)-stereoisomers of bicyclic nucleosides T and U were successfully synthesized following Vorbrüggen nucleobase coupling of T and U with triacetylated glycosyl donor obtained from acetolysis of (5R)-and (5 S)-4-C-(tert-butyldiphenylsilyloxymethyl)-5-C-methyl-1,2-O-isopropylidene-3-O-(2-naphthylmethyl)-α-D-xylofuranoses and further cyclization and deprotection of the resulted nucleoside. One of the nucleosides, (6'R)-6'-methyl-2'-O,4'-C-methylene-α-L-ribofuranosyl-uracil has been reported earlier in 1.8% yield, while the present methodology yielded the nucleoside in 5.4% yield. All the synthesized 6'-Me-bicyclic-nucleosides showed no significant anti-viral activity against H1 N1 strain of influenza A virus (A/Puerto Rico/ 8/1934). Experimental procedures including materials, reagents and solvents used for the synthesis of compounds 1, 2, 3 a, 3 b, (5R)-4, (5S)-5, (5R)-6, (5S)-7, 8 ad , 9 ad , 10 ad , 11 ad , 12 ad and 13 ad and their characterization data along with their 1 H and 13 C NMR spectra are given in the supplementary information.
Journal of Medicinal Chemistry, 1976
Reaction of the trimethylsilyl derivative of 2,3-dihydro-6H-l,3-oxazine-2,6-dione (2, "uracil anhydride") with protected 1-0-acetylribofuranoses in the presence of stannic chloride gave the corresponding blocked nucleosides. 3-(2,3,-5-Tri-0-2',2',2'-trichloroethoxycarbonyl-~-~-ribofuranosyl)-2,3-dihydro-6H-l,3-oxazine-2,6-dione (4c) thus prepared from the protected sugar 3c, 1-0-acetyl-2,3,5-tri-0-(2,2,2-trichloroethoxycarbonyl)ribofuranose, gave, on removal of the protecting groups with zinc dust, 3-(~-~ribofuranosyl)-2,3-dihydro-6H-l,3-oxazine-2,6-dione (1). The structure of 1 was confirmed by uv, ir, NMR, and CD spectral data and was shown to be an N nucleoside. Uracil anhydride, 2, and, to a lesser extent, its ribonucleoside 1 exert a moderate growth inhibition of mouse leukemia L5178Y, HeLa, and Novikoff hepatoma cells in culture. Both compounds produce weak inhibition of vaccinia viral replication in HeLa cells.
Carbohydrate Research, 1995
Methyl 5-O-acetyl-3-azido-2,3-dideoxy-4-thio-a,fl-D-erythro-pentofuranoside and 1,5-O-diacetyl-3-azido-2,3-dideoxy-4-thio-a,[J-D-erythro-pentofuranose were prepared in twelve and thirteen steps, respectively, by an efficient route starting from D-xylose. Both compounds were easily converted into an anomeric mixture of pyrimidine nucleosides by reaction with the 2,4-bi(trimethylsilyloxy) derivative in the presence of a Lewis acid. The anomeric mixtures were separated by chromatography. The 4'-thio analogue of AZT and related uridine nucleosides have been prepared by a novel and more efficient approach.
Journal of Chemical Research, 2007
A series of new uracil non-nucleosides analogues of S-DABO's was synthesised by reaction of 5-alkyl-6-(p-chlorobenzyl)-2-thiouracils with chloroethyl dialkylamine hydrochloride, N-(2-chloroethyl)-pyrrolidine hydrochloride, N-(2-chloroethyl)-piperidine hydrochloride or appropriate haloethers. Novel emivirine analogues were synthesised by silylation of 5-alkyl-6-(p-chlorobenzyl)uracils and treatment with bromomethyl methyl ether, chloromethyl ethyl ether or benzyl chloromethyl ether. Compounds 6-(p-chlorobenzyl)-5-ethyl-1-ethyloxymethyluracil (9d) and 1-benzyloxymethyl-6-(4-chlorobenzyl)-5-ethyluracil (9f) showed activity against wild-type HIV-1 strain III B in MT-4 cells.
Chemical synthesis of 4′-thio and 4′-sulfinyl pyrimidine nucleoside analogues
Organic and Biomolecular Chemistryistry, 2021
Analogues of the canonical nucleosides required for nucleic acid synthesis have a longstanding presence and proven capability within antiviral and anticancer research. 4'-Thionucleosides, that incorporate bioisosteric replacement of furanose oxygen with sulfur, represent an important chemotype within this field. Established herein is synthetic capability towards a common 4-thioribose building block that enables access to thio-ribo and thio-arabino pyrimidine nucleosides, alongside their 4'-sulfinyl derivatives. In addition, this building block methodology is templated to deliver 4'-thio and 4'-sulfinyl analogues of the established anticancer drug gemcitabine. Cytotoxic capability of these new analogues is evaluated against human pancreatic cancer and human primary glioblastoma cell lines, with observed activities ranging from low μM to >200 μM; explanation for this reduced activity, compared to established nucleoside analogues, is yet unclear. Access to these chemotypes, with thiohemiaminal linkages, will enable a wider exploration of purine and triphosphate analogues and the application of such materials for potential resistance towards relevant hydrolytic enzymes within nucleic acid biochemistries.
Synthesis of Purine and Pyrimidine 3‘-Amino-3‘-deoxy- and 3‘-Amino-2‘,3‘-dideoxyxylonucleosides
The Journal of Organic Chemistry, 1996
A general procedure to obtain the 3′-aminoxylonucleosides 13a,b and 17a,b is presented. The synthetic scheme is based on the 5′ directed intramolecular nucleophilic substitution at the 3′activated position of the nucleoside. The approach of the incoming group to this position takes place regio-and stereoselectively from the most hindered face of the nucleoside. The methodology presented is applicable to ribonucleosides and 2′-deoxyribonucleosides, regardless of their nitrogenated base.